There is a relative lack of observational data on the outcomes or effectiveness of screening programs for siblings of patients with VUR, and an adequate, randomized, controlled trial of sibling screening seems unlikely.6
Therefore, any decision regarding VUR screening programs for siblings without symptoms must be made on the basis of imperfect information. In the absence of large clinical trials or observational studies, clinicians must base their decisions to screen siblings without symptoms on the potential benefits and risks of screening a given patient. In the application of imperfect information to population-level decisions such as screening regimens, decision analysis models such as ours can be helpful for identifying the decision that is most likely to result in favorable patient outcomes and the parameters that may influence those outcomes significantly. This is of significance to pediatric practitioners, given the ubiquity of VUR among children and the likelihood that children with VUR will have ≥1 sibling without symptoms.
In this model of 2 hypothetical cohorts of siblings (without symptoms) of patients with VUR, we found that a universal VUR screening program was associated invariably with increased medical costs and increased radiation doses for the screened siblings. However, the effectiveness of such a program (ie, its ability to reduce the number of fUTIs among screened siblings) varied significantly according to the presumed effectiveness of antibiotic prophylaxis in preventing fUTIs and the age at which siblings were screened. In our base case analysis of 100 000 siblings 1 year of age without symptoms, universal screening would prevent ~3400 fUTIs, on the basis of the assumption that antibiotic prophylaxis is effective. That is, 30 siblings without symptoms would need to be screened for prevention of an initial fUTI in a single patient.
Unfortunately, the true effectiveness of antimicrobial prophylaxis in fUTI prevention for patients with VUR is uncertain. One systematic review found a statistically significant 56% reduction in UTI rates with prophylaxis,9
whereas another found only a nonsignificant 4% reduction in the likelihood of UTI.8
Importantly, although both reviews were performed by using acceptable methods, they both included heterogeneous populations, which indicates that neither review may reflect accurately the true effectiveness of antibiotics.
In this case, the prevention of fUTIs, and thus the reduction in risk of renal damage, is the obvious goal of a screening regimen for siblings without symptoms. This is a laudable goal, and the costs of screening must be balanced against the benefits. If it is assumed that antibiotic prophylaxis is effective in preventing fUTIs (as indicated by Williams et al9
), then the NNS would be 30 patients 1 year of age and the conservatively estimated costs of screening would be $187 million, or $55 600 per averted fUTI. If the effectiveness of prophylaxis was reduced, however, then the number of fUTIs would be increased proportionately, whereas the cost of the overall screening regimen would increase because of the cost of treating those infections. If antibiotic prophylaxis is ineffective (as indicated by Mori et al8
), then the NNS would increase to 429 children, whereas the screening costs would increase to $191 million, or $819 000 per averted fUTI. As the effectiveness of antibiotic prophyl axis decreases, so does the cost-effectiveness of universal sibling screening. Future randomized trials, such as the ongoing Randomized Intervention for Children With Vesicoureteral Reflux study,19
should provide more-robust estimates of the effectiveness of prophylaxis. Until then, clinicians must rely on imperfect data to decide whether the true cost of VUR screening for siblings without symptoms is justified, knowing that the true NNS lies some where between 30 and 430 children and that the true cost of screening likely lies somewhere between $56 000 and $820 000 per averted fUTI.
Among the potential risks of screening, the radiation-associated outcomes bear mention. Cystourethrography, particularly cVCUG, is associated with a relatively high per-patient dose of ionizing radiation, compared with a low-dose testing method such as RNC.13
Although the long-term risks of low-dose radiation are small, they are not immaterial.14,20
This increased ionizing radiation exposure can be translated in to a small but measurable increase in long-term risk of radiation-related cancer development, particularly as applied to large populations, as estimated by the National Research Council.21
With the assumption of a linear, no-threshold model of cancer risk as a result of low-dose ionizing radiation, the risk of contracting a lethal cancer is ~1 in 20 000 per mSv for an adult. However, children exposed to radiation are presumed to be at higher risk than adults, because of the greater radiosensitivity of growing tissues and children’s longer life expectancy. Screening 100 000 siblings 1 year of age without symptoms for VUR would be expected to result in 1.7 radiation-induced lethal solid abdominal tumors. In terms of the natural incidence of cancer, this number is tiny; by comparison, ~42 000 of the 100 000 children in our cohort would be expected to develop a lethal cancer resulting from other causes during the course of their lifetimes.21
Therefore, the question to be considered is whether the clinical information gained through the use of a universal screening regimen is great enough to offset the low but measurable risks of the increased radiation dose, particularly in the context of increased medical use of ionizing radiation throughout the nation.14,22,23
Similarly, the risks of treatment, including those of antibiotic prophylaxis, must be considered. The risk of cutaneous reactions among children taking trimethoprim-sulfamethoxazole is 1.4% to 7.4% per year of prophylaxis.24
In our analysis, a screened cohort of 100 000 siblings 1 year of age without symptoms, monitored for 18 years, would be expected to accrue 181 571 person-years of antibiotic prophylaxis, and between 2500 and 13 400 dermatologic reactions over that time span would be expected. Although the overwhelming majority of these complications would be self-limited urticaria or maculopapular rash, more-significant problems, such as Stevens-Johnson syndrome, have been reported. As with cost and radiation exposure, these rare risks of screening must be weighed against a possible decreased risk of renal scarring, hypertension, and renal insufficiency among siblings with VUR.
In evaluating any screening program, it is important to examine the effects of lead-time, length-time, and overdiagnosis biases. Lead- and length-time biases refer to the likelihood of screening programs to overestimate survival benefits of screening and to detect preferentially slowly progressive disease. Because VUR resolves over time, these biases seem unlikely to be pertinent to VUR. Overdiagnosis bias is the screening-related detection of subclinical disease that would not otherwise have become clinically apparent, as reflected in the NNS (30–430 siblings would need to be screened to avert 1 fUTI).
The results of this analysis must be interpreted in light of its limitations. All parameter estimates were based on the existing urological literature; therefore, they reflect any methodological limitations and biases present in that literature. Similarly, all of our cost estimates (particularly for physician time and imaging studies) were based on nationally weighted averages.15
Although this method has many advantages and is recommended by many authors,16
national values may not be generalizable to all geographic areas, particularly those outside the United States. Lastly, our analysis extended only to 18 years of age and focused on the more-proximal outcomes of fUTIs. We did not include costs and outcomes associated with renal scarring and renal failure, which might be prevented through an aggressive VUR screening program.